Histidine-rich glycoprotein (HRG) is a
glycoprotein that in humans is encoded by the HRGgene.[5][6] The HRG protein is produced in the liver, and it could also be synthesized by
monocytes,
macrophages, and
megakaryocytes.[7] It possesses a multi-
domain structure, which makes it capable of binding to numerous ligands and modulating various biological processes including
immunity,
vascularization and
coagulation.[8]
Structure
Gene
The HRG gene lies on location of 3q27 on the
chromosome 3, spans approximately 11kb, and consist of 7
exons. Two common
isoforms of the HRG gene have been found in humans. These isoforms exist due to a
polymorphism occurring in exon 5.[9]
Protein
HRG is a glycoprotein of 70-75kDa present at a relatively high concentration in the plasma of
vertebrates. The primary structure of human HRG is predicted to be a 507
amino acid multidomain
polypeptide consisting of two cystatin-like regions at the
N-terminus, a histidine-rich region (HRR) flanked by proline-rich regions (PRR), and a
C-terminal domain.[10] HRG has an unusually high concentration of
histidine and
proline residues, each constituting approximately 13% of total amino acids, concentrated within the HRR and PRR.[11][12][13] The high concentration of both histidine and proline residues has resulted in HRG also being termed 'histidine–proline-rich glycoprotein' (HPRG).[14] Human HRG is also composed of approximately 14%
carbohydrate attached to six predicted N-linked
glycosylation sites.[10]
The implications of HRG in cancer have been described as "multi-faceted".[18] For example, the protein appears to have both pro- and anti-
angiogenic effects. In biomarker studies, the protein has been found to have potential prognostic and diagnostic value for cancer.[18] Furthermore, the absence of the protein is associated with
thrombophilia.[18] HRG has also been shown to inhibit the M2-like phenotype of
tumor-associated macrophages.[19]
In addition, HRG has been discovered to play a role in infection. Some studies have found HRG has the antibacterial activity against Streptococcus pyogenes and a direct interaction between a S. pyogenes virulence factor (sHIP) and the human HRG has been identified.[18][20]
^
abBlank M, Shoenfeld Y (June 2008). "Histidine-rich glycoprotein modulation of immune/autoimmune, vascular, and coagulation systems". Clinical Reviews in Allergy & Immunology. 34 (3): 307–12.
doi:
10.1007/s12016-007-8058-6.
PMID18219588.
S2CID37799666.
^Hennis BC, van Boheemen PA, Wakabayashi S, Koide T, Hoffmann JJ, Kievit P, Dooijewaard G, Jansen JG, Kluft C (December 1995). "Identification and genetic analysis of a common molecular variant of histidine-rich glycoprotein with a difference of 2kD in apparent molecular weight". Thrombosis and Haemostasis. 74 (6): 1491–6.
doi:
10.1055/s-0038-1649971.
PMID8772226.
S2CID44971634.
^
abKoide T, Foster D, Yoshitake S, Davie EW (April 1986). "Amino acid sequence of human histidine-rich glycoprotein derived from the nucleotide sequence of its cDNA". Biochemistry. 25 (8): 2220–5.
doi:
10.1021/bi00356a055.
PMID3011081.
^Haupt H, Heimburger N (July 1972). "[Human serum proteins with high affinity for carboxymethylcellulose. I. Isolation of lysozyme, C1q and 2 hitherto unknown -globulins]". Hoppe-Seyler's Zeitschrift für Physiologische Chemie. 353 (7): 1125–32.
doi:
10.1515/bchm2.1972.353.2.1125.
PMID4116336.
^Koide T, Odani S, Ono T (November 1985). "Human histidine-rich glycoprotein: simultaneous purification with antithrombin III and characterization of its gross structure". Journal of Biochemistry. 98 (5): 1191–200.
doi:
10.1093/oxfordjournals.jbchem.a135385.
PMID4086476.
^Borza DB, Tatum FM, Morgan WT (February 1996). "Domain structure and conformation of histidine-proline-rich glycoprotein". Biochemistry. 35 (6): 1925–34.
doi:
10.1021/bi952061t.
PMID8639676.
^
abMorgan WT (August 1978). "Human serum histidine-rich glycoprotein. I. Interactions with heme, metal ions and organic ligands". Biochimica et Biophysica Acta (BBA) - Protein Structure. 535 (2): 319–33.
doi:
10.1016/0005-2795(78)90098-3.
PMID678554.
^Morgan WT (March 1981). "Interactions of the histidine-rich glycoprotein of serum with metals". Biochemistry. 20 (5): 1054–61.
doi:
10.1021/bi00508a002.
PMID7225317.
van den Berg EA, le Clercq E, Kluft C, Koide T, van der Zee A, Oldenburg M, Wijnen JT, Meera Khan P (June 1990). "Assignment of the human gene for histidine-rich glycoprotein to chromosome 3". Genomics. 7 (2): 276–9.
doi:
10.1016/0888-7543(90)90551-5.
PMID2347592.
Koide T, Foster D, Yoshitake S, Davie EW (April 1986). "Amino acid sequence of human histidine-rich glycoprotein derived from the nucleotide sequence of its cDNA". Biochemistry. 25 (8): 2220–5.
doi:
10.1021/bi00356a055.
PMID3011081.
Heimburger N, Haupt H, Kranz T, Baudner S (July 1972). "[Human serum proteins with high affinity to carboxymethylcellulose. II. Physico-chemical and immunological characterization of a histidine-rich 3,8S- 2 -glycoportein (CM-protein I)]". Hoppe-Seyler's Zeitschrift für Physiologische Chemie. 353 (7): 1133–40.
doi:
10.1515/bchm2.1972.353.2.1133.
PMID4116337.
Hennis BC, Frants RR, Bakker E, Vossen RH, van der Poort EW, Blonden LA, Cox S, Khan PM, Spurr NK, Kluft C (January 1994). "Evidence for the absence of intron H of the histidine-rich glycoprotein (HRG) gene: genetic mapping and in situ localization of HRG to chromosome 3q28-q29". Genomics. 19 (1): 195–7.
doi:
10.1006/geno.1994.1046.
PMID8188234.
Sørensen CB, Krogh-Pedersen H, Petersen TE (August 1993). "Determination of the disulphide bridge arrangement of bovine histidine-rich glycoprotein". FEBS Letters. 328 (3): 285–90.
doi:
10.1016/0014-5793(93)80945-Q.
PMID8348977.
S2CID11051275.
Leung L (May 1993). "Histidine-rich glycoprotein: an abundant plasma protein in search of a function". The Journal of Laboratory and Clinical Medicine. 121 (5): 630–1.
PMID8478589.
Angles-Cano E, Gris JC, Loyau S, Schved JF (May 1993). "Familial association of high levels of histidine-rich glycoprotein and plasminogen activator inhibitor-1 with venous thromboembolism". The Journal of Laboratory and Clinical Medicine. 121 (5): 646–53.
PMID8478593.
Gorgani NN, Parish CR, Easterbrook Smith SB, Altin JG (June 1997). "Histidine-rich glycoprotein binds to human IgG and C1q and inhibits the formation of insoluble immune complexes". Biochemistry. 36 (22): 6653–62.
doi:
10.1021/bi962573n.
PMID9184145.
Wakabayashi S, Takahashi K, Koide T (March 1999). "Structural characterization of the gene for human histidine-rich glycoprotein, reinvestigation of the 5'-terminal region of cDNA and a search for the liver specific promoter in the gene". Journal of Biochemistry. 125 (3): 522–30.
doi:
10.1093/oxfordjournals.jbchem.a022316.
PMID10050040.
Histidine-rich glycoprotein (HRG) is a
glycoprotein that in humans is encoded by the HRGgene.[5][6] The HRG protein is produced in the liver, and it could also be synthesized by
monocytes,
macrophages, and
megakaryocytes.[7] It possesses a multi-
domain structure, which makes it capable of binding to numerous ligands and modulating various biological processes including
immunity,
vascularization and
coagulation.[8]
Structure
Gene
The HRG gene lies on location of 3q27 on the
chromosome 3, spans approximately 11kb, and consist of 7
exons. Two common
isoforms of the HRG gene have been found in humans. These isoforms exist due to a
polymorphism occurring in exon 5.[9]
Protein
HRG is a glycoprotein of 70-75kDa present at a relatively high concentration in the plasma of
vertebrates. The primary structure of human HRG is predicted to be a 507
amino acid multidomain
polypeptide consisting of two cystatin-like regions at the
N-terminus, a histidine-rich region (HRR) flanked by proline-rich regions (PRR), and a
C-terminal domain.[10] HRG has an unusually high concentration of
histidine and
proline residues, each constituting approximately 13% of total amino acids, concentrated within the HRR and PRR.[11][12][13] The high concentration of both histidine and proline residues has resulted in HRG also being termed 'histidine–proline-rich glycoprotein' (HPRG).[14] Human HRG is also composed of approximately 14%
carbohydrate attached to six predicted N-linked
glycosylation sites.[10]
The implications of HRG in cancer have been described as "multi-faceted".[18] For example, the protein appears to have both pro- and anti-
angiogenic effects. In biomarker studies, the protein has been found to have potential prognostic and diagnostic value for cancer.[18] Furthermore, the absence of the protein is associated with
thrombophilia.[18] HRG has also been shown to inhibit the M2-like phenotype of
tumor-associated macrophages.[19]
In addition, HRG has been discovered to play a role in infection. Some studies have found HRG has the antibacterial activity against Streptococcus pyogenes and a direct interaction between a S. pyogenes virulence factor (sHIP) and the human HRG has been identified.[18][20]
^
abBlank M, Shoenfeld Y (June 2008). "Histidine-rich glycoprotein modulation of immune/autoimmune, vascular, and coagulation systems". Clinical Reviews in Allergy & Immunology. 34 (3): 307–12.
doi:
10.1007/s12016-007-8058-6.
PMID18219588.
S2CID37799666.
^Hennis BC, van Boheemen PA, Wakabayashi S, Koide T, Hoffmann JJ, Kievit P, Dooijewaard G, Jansen JG, Kluft C (December 1995). "Identification and genetic analysis of a common molecular variant of histidine-rich glycoprotein with a difference of 2kD in apparent molecular weight". Thrombosis and Haemostasis. 74 (6): 1491–6.
doi:
10.1055/s-0038-1649971.
PMID8772226.
S2CID44971634.
^
abKoide T, Foster D, Yoshitake S, Davie EW (April 1986). "Amino acid sequence of human histidine-rich glycoprotein derived from the nucleotide sequence of its cDNA". Biochemistry. 25 (8): 2220–5.
doi:
10.1021/bi00356a055.
PMID3011081.
^Haupt H, Heimburger N (July 1972). "[Human serum proteins with high affinity for carboxymethylcellulose. I. Isolation of lysozyme, C1q and 2 hitherto unknown -globulins]". Hoppe-Seyler's Zeitschrift für Physiologische Chemie. 353 (7): 1125–32.
doi:
10.1515/bchm2.1972.353.2.1125.
PMID4116336.
^Koide T, Odani S, Ono T (November 1985). "Human histidine-rich glycoprotein: simultaneous purification with antithrombin III and characterization of its gross structure". Journal of Biochemistry. 98 (5): 1191–200.
doi:
10.1093/oxfordjournals.jbchem.a135385.
PMID4086476.
^Borza DB, Tatum FM, Morgan WT (February 1996). "Domain structure and conformation of histidine-proline-rich glycoprotein". Biochemistry. 35 (6): 1925–34.
doi:
10.1021/bi952061t.
PMID8639676.
^
abMorgan WT (August 1978). "Human serum histidine-rich glycoprotein. I. Interactions with heme, metal ions and organic ligands". Biochimica et Biophysica Acta (BBA) - Protein Structure. 535 (2): 319–33.
doi:
10.1016/0005-2795(78)90098-3.
PMID678554.
^Morgan WT (March 1981). "Interactions of the histidine-rich glycoprotein of serum with metals". Biochemistry. 20 (5): 1054–61.
doi:
10.1021/bi00508a002.
PMID7225317.
van den Berg EA, le Clercq E, Kluft C, Koide T, van der Zee A, Oldenburg M, Wijnen JT, Meera Khan P (June 1990). "Assignment of the human gene for histidine-rich glycoprotein to chromosome 3". Genomics. 7 (2): 276–9.
doi:
10.1016/0888-7543(90)90551-5.
PMID2347592.
Koide T, Foster D, Yoshitake S, Davie EW (April 1986). "Amino acid sequence of human histidine-rich glycoprotein derived from the nucleotide sequence of its cDNA". Biochemistry. 25 (8): 2220–5.
doi:
10.1021/bi00356a055.
PMID3011081.
Heimburger N, Haupt H, Kranz T, Baudner S (July 1972). "[Human serum proteins with high affinity to carboxymethylcellulose. II. Physico-chemical and immunological characterization of a histidine-rich 3,8S- 2 -glycoportein (CM-protein I)]". Hoppe-Seyler's Zeitschrift für Physiologische Chemie. 353 (7): 1133–40.
doi:
10.1515/bchm2.1972.353.2.1133.
PMID4116337.
Hennis BC, Frants RR, Bakker E, Vossen RH, van der Poort EW, Blonden LA, Cox S, Khan PM, Spurr NK, Kluft C (January 1994). "Evidence for the absence of intron H of the histidine-rich glycoprotein (HRG) gene: genetic mapping and in situ localization of HRG to chromosome 3q28-q29". Genomics. 19 (1): 195–7.
doi:
10.1006/geno.1994.1046.
PMID8188234.
Sørensen CB, Krogh-Pedersen H, Petersen TE (August 1993). "Determination of the disulphide bridge arrangement of bovine histidine-rich glycoprotein". FEBS Letters. 328 (3): 285–90.
doi:
10.1016/0014-5793(93)80945-Q.
PMID8348977.
S2CID11051275.
Leung L (May 1993). "Histidine-rich glycoprotein: an abundant plasma protein in search of a function". The Journal of Laboratory and Clinical Medicine. 121 (5): 630–1.
PMID8478589.
Angles-Cano E, Gris JC, Loyau S, Schved JF (May 1993). "Familial association of high levels of histidine-rich glycoprotein and plasminogen activator inhibitor-1 with venous thromboembolism". The Journal of Laboratory and Clinical Medicine. 121 (5): 646–53.
PMID8478593.
Gorgani NN, Parish CR, Easterbrook Smith SB, Altin JG (June 1997). "Histidine-rich glycoprotein binds to human IgG and C1q and inhibits the formation of insoluble immune complexes". Biochemistry. 36 (22): 6653–62.
doi:
10.1021/bi962573n.
PMID9184145.
Wakabayashi S, Takahashi K, Koide T (March 1999). "Structural characterization of the gene for human histidine-rich glycoprotein, reinvestigation of the 5'-terminal region of cDNA and a search for the liver specific promoter in the gene". Journal of Biochemistry. 125 (3): 522–30.
doi:
10.1093/oxfordjournals.jbchem.a022316.
PMID10050040.